In vitro leishmanicidal activity of imidazole- or pyrazole-based benzo[g]phthalazine derivatives against Leishmania infantum and Leishmania braziliensis species

Sánchez‐Moreno, Manuel; Gómez-Contreras, Fernando; Navarro, Pilar; Marı́n, Clotilde; Ramírez-Macías, Inmaculada; Olmo, F.J.; Sanz, A.; Campayo, Lucrecia; Cano, Carolina; Yunta, María J. R.

doi:10.1093/jac/dkr480

Cited by 75 publications

(50 citation statements)

References 26 publications

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“…Huge membrane and intracellular damages induced by compound 1 but not by the poorly efficient compound 3 were evidenced using TEM. In other studies reporting the effect of drugs like HePC and diterpenoid alkaloids, parasite death seems to result from intracellular damages rather than primary membrane damage (37,45). This is consistent with the results of our cytotoxicity assay using CellTox green dye, which can efficiently enter cells and bind to DNA only in the presence of membrane alterations.…”

Section: Discussionsupporting

confidence: 92%

“…Therefore, novel therapeutic approaches, particularly those aimed at exploring new horizons for the development of efficient antileishmanial molecules, are required (37)(38)(39). Current advances in our understanding of the biosynthesis of Galf-containing glycoconjugates have opened a new field of research, since these compounds are found at the surface of several widespread human pathogens, including Leishmania (13).…”

Section: Discussionmentioning

confidence: 99%

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Alkyl Galactofuranosides Strongly Interact with Leishmania donovani Membrane and Provide Antileishmanial Activity

Suleman

Gangneux

Legentil

et al. 2014

Antimicrob Agents Chemother

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fWe investigated the in vitro effects of four alkyl-galactofuranoside derivatives, i.e., octyl-␤-D-galactofuranoside (compound 1), 6-amino-␤-D-galactofuranoside (compound 2), 6-N-acetamido-␤-D-galactofuranoside (compound 3), and 6-azido-␤-D-galactofuranoside (compound 4), on Leishmania donovani. Their mechanism of action was explored using electron paramagnetic resonance spectroscopy (EPR) and nuclear magnetic resonance (NMR), and ultrastructural alterations were analyzed by transmission electron microscopy (TEM). Compound 1 showed the most promising effects by inhibiting promastigote growth at a 50% inhibitory concentration (IC 50 ) of 8.96 ؎ 2.5 M. All compounds exhibit low toxicity toward human macrophages. Compound 1 had a higher selectivity index than the molecule used for comparison, i.e., miltefosine (159.7 versus 37.9, respectively). EPR showed that compound 1 significantly reduced membrane fluidity compared to control promastigotes and to compound 3. The furanose ring was shown to support this effect, since the isomer galactopyranose had no effect on parasite membrane fluidity or growth. NMR showed a direct interaction of all compounds (greatest with compound 1, followed by compounds 2, 3, and 4, in descending order) with the promastigote membrane and with octyl-galactopyranose and octanol, providing evidence that the n-octyl chain was primarily involved in anchoring with the parasite membrane, followed by the putative crucial role of the furanose ring in the antileishmanial activity. A morphological analysis of compound 1-treated promastigotes by TEM revealed profound alterations in the parasite membrane and organelles, but this was not the case with compound 3. Quantification of annexin V binding by flow cytometry confirmed that compound 1 induced apoptosis in >90% of promastigotes. The effect of compound 1 was also assessed on intramacrophagic amastigotes and showed a reduction in amastigote growth associated with an increase of reactive oxygen species (ROS) production, thus validating its promising effect.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Alkyl Galactofuranosides Strongly Interact with Leishmania donovani Membrane and Provide Antileishmanial Activity

Suleman

Gangneux

Legentil

et al. 2014

Antimicrob Agents Chemother

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“…The cytotoxicity test on macrophages was performed according to the method described by Ref. [15]. After 72 h of treatment with 100, 50, 25, l0, and 1 mM of product, cell viability was determined by flow cytometry.…”

Section: Cell Culture and Cytotoxicity Testsmentioning

confidence: 99%

In vitro activity of scorpiand-like azamacrocycle derivatives in promastigotes and intracellular amastigotes of Leishmania infantum and Leishmania braziliensis

Marı́n

Clares

Ramírez-Macías

et al. 2013

European Journal of Medicinal Chemistry

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“…The chemical versatility of the pyrazole and its analogues has attracted interest because it allows a range of applications in the pharmaceutical industry. Many pyrazole-derived compounds are known to exhibit anticancer [6][7][8][9][10], antimicrobial [11,12], antiviral [13], antiparasitic [14], anti-inflammatory [15,16], antipyretic [17], analgesic [18], anticoagulant [19], and anti-obesity [20] biological activities. The pyridine nucleus is a key constituent, present in a range of bioactive compounds, occurring both synthetically and naturally with wide range of biological applications [21,22].…”

Section: Introductionmentioning

confidence: 99%

An Efficient Synthesis of Novel Pyrazole-Based Heterocycles as Potential Antitumor Agents

et al. 2017

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Abstract:A new series of pyrazolylpyridines was prepared by reaction of ethyl-3-acetyl-1,5-diphenyl-1H-pyrazole-4-carboxylate with the appropriate aldehyde, malononitrile, or ethyl acetoacetate and an excess of ammonium acetate under reflux in acetic acid. Similarly, two novel bipyridine derivatives were prepared by the above reaction using terephthaldehyde in lieu of benzaldehyde derivatives. In addition, a series of 1,2,4-triazolo[4,3-a]pyrimidines was synthesized by a reaction of 6-(pyrazol-3-yl)pyrimidine-2-thione with a number of hydrazonoyl chlorides in dioxane and in the presence of triethylamine. The structure of the produced compounds was established by elemental analyses and spectral methods, and the mechanisms of their formation was discussed. Furthermore, the pyrazolyl-pyridine derivatives were tested as anticancer agents and the results obtained showed that some of them revealed high activity against human hepatocellular carcinoma (HEPG2) cell lines.

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In vitro leishmanicidal activity of imidazole- or pyrazole-based benzo[g]phthalazine derivatives against Leishmania infantum and Leishmania braziliensis species

Abstract: All the compounds assayed were active in vitro against the two Leishmania species and were less toxic against mammalian cells than the reference drug, but the monosubstituted compounds were significantly more effective and less toxic than their disubstituted counterparts.

Cited by 75 publications

References 26 publications

Alkyl Galactofuranosides Strongly Interact with Leishmania donovani Membrane and Provide Antileishmanial Activity

Alkyl Galactofuranosides Strongly Interact with Leishmania donovani Membrane and Provide Antileishmanial Activity

In vitro activity of scorpiand-like azamacrocycle derivatives in promastigotes and intracellular amastigotes of Leishmania infantum and Leishmania braziliensis

An Efficient Synthesis of Novel Pyrazole-Based Heterocycles as Potential Antitumor Agents

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